We are indeed fortunate to have an opportunity to speak with Dr. Bauman about her work in clinical and basic research at the Lurie Family Autism Center/Learning and Developmental Disabilities Evaluation and Rehabilitation Services (LADDERS). In the interview that follows, Dr. Bauman reveals her current and past work as a pediatric neurologist, her thoughts on the increasing prevalence of autism, the role of auto-immune factors in the development of autism, and the direction she would like to see autism research move in the near future. Dr. Bauman leaves parents with a hopeful message that early diagnosis, early treatment and intensive services with high quality, experienced professionals can really turn around many children with autism spectrum disorders and can result in much brighter futures for these children and their families.
How did you first get involved in autism research and clinical treatment?
My interest in autism was an accident. When I was a resident I remember thinking that autism was a totally impossible problem. I couldn’t understand how you could even begin to think about it. However, during my residency program at the Massachusetts General Hospital (MGH) in Boston, MA, I was privileged to be able to spend 6 months working with Dr. Paul Yakovlev, MD whose long and very productive career involved studies of the human postmortem brain during development, aging and in a number neurological disorders. It was during this time that I learned about the neuroanatomy and neuropathology of the brain and met my eventual research colleague, Dr. Thomas Kemper. While working in this laboratory, Dr. Kemper and I conducted a neuroanatomical study of the brain in Phenyketonuria (PKU), a genetic disorder that is characterized by an inability of the body to utilize the essential amino acid phenylalanine, which was eventually published in 1982.
After leaving Dr. Yakovlev’s laboratory and my residency training, I spent much of my time seeing patients with a variety of neurological and developmental disorders, primarily those with learning disabilities and seizure disorders. About a year after Tom and I finished the phenylketonuria project, I felt that I needed to move beyond the clinic setting. By that time, Tom had moved over to Boston University School of Medicine (BUSM). One day, while visiting him in his laboratory, I said, “I need to get out of the clinic, would you mind if I spent some time in your Lab? I don’t have any time, I don’t any money, but I need to do something different.” I cannot tell you to this day why I said this, I said, “You don’t have a case of autism do you?” Happily, Tom agreed and suggested that I begin to work on the postmortem brain obtained from a young man with autism who had died by accidental drowning. This case had been available for study for five years and had remained uninvestigated. That was the summer of 1983. So I started to analyze the stained sections of this case using a comparison microscope – essentially two microscopes put side by side and connected by a bridge, thus allowing the evaluation of two separate brain sections, side-by-side. Using this microscope, we were able to look at identical sections of an age and sex-matched control case and the autism brain. It quickly became very clear that there were some distinct anatomical abnormalities in the autistic brain. The results of our study of this autism brain were subsequently reported at the meeting of the American Academy of Neurology in the spring of 1984. This was the first detailed report of brain abnormalities in the autistic brain. We received many letters from parents and families of autistic individuals that basically said, “Thank you for proving that this isn’t the result of bad parenting.” Up to that point, Bruno Bettelheim’s “refrigerator mother” theory was still a widespread belief and suggested that autistic behaviors stemmed from the emotional frigidity of the children’s mothers.
Following this initial study, we were told that we should seek funding from the NIH to continue our investigations of the autistic brain. We tried to submit some grants to the National Institute of Health but they weren’t interested. At that time, there were very few postmortem autism brains available for study and it cost approximately $6,000 to embed, section and stain just one brain. I then met Mrs. Nancy Lurie Marks, the person who has recently given a substantial gift to support and expand the current LADDERS/MGH program. Mrs. Marks was the first person who funded our neuroanatomic research and was the person who really helped me to get started in my research career, a career path that I continue to enjoy to the present time. Our techniques have changed with the advancement in technology but we continue to seek a better understanding of the neurobiology of the autistic brain and its impact on behavior, cognition, language and social interaction.
Early in my clinical career, I was particularly interested in working with children with learning disabilities. In 1981, I was recruited by the Youville Hospital in Cambridge, MA to lead their then fairly small outpatient children’s rehabilitation clinic. Over time, the program grew and eventually was moved out of the main hospital into their school of nursing. The program continued to grow and began to include children with learning disabilities and other developmental disorders. Following the publication of our basic science research relating to studies of the autistic brain, the referrals of children with autism and related disorders began to increase and eventually became the majority of patients seen at LADDERS. Although the program is largely known because of its work with children, adolescents and adults with autism, LADDERS continues to see patients of all ages with a wide variety of learning, neurological and developmental disorders.
What are your thoughts on the dramatic rate of increase of autism spectrum disorders?
There are a number of opinions as to why there appears to be a dramatic increase in children diagnosed with autism and the truth is that no one really knows for sure. Back in the 70s and 80s, the terms “Asperger’s syndrome” and “Pervasive Developmental Disorder” were not available or used. At that time, most of the children labeled as “autistic” were those who would sit in a corner, rock back and forth, demonstrate poor eye contact and arm flapping and were non-verbal. LADDERS see approximately 4,000 patient visits annually. It is an extremely rare day that we see such a child anymore. Where did those children go? We could hypothesize that we are identifying children at risk much earlier and providing them with intensive interventions, thus essentially avoiding or eliminating the previously characteristic severe behaviors in the majority of autistic children. Alternatively, we could hypothesize that “autism” as we once knew it, has really declined in prevalence. What we once called the kind of child who came to most of us in the office now, is hard to define in retrospect. Some may have simply been called “mentally retarded.” Others may have been considered to have had “childhood schizophrenia,” a term which is rarely if ever used now.
It should also be recalled that, until the middle to late 80s, the cause of “autism” was blamed on poor mothering or the “refrigerator mother,” a term coined by Bruno Bettleheim. Thus, if a child was labeled “autistic” it was assumed that it was his mother’s fault. Understandably, giving a child this diagnosis was difficult at best and often resulted in the institutionalization of that child. School and home-based programs as we now know them did not exist. Happily, since that time, research has shown us that autism is a neurodevelopmental disorder and much of the data suggests that it begins before birth. Further, clinical research has helped to develop clinical measures and observational tools that allow us to fairly accurately diagnose children at risk for autism as early as 14 months of age. Newer tools are in the process of development that, if perfected, may allow us to identify high risk children as early as 6 months of age. There are now numerous studies which have shown the significant benefits of intensive early intervention programs for ASD children and the improved developmental outcomes when such services are provided. Currently, a child carrying an ASD diagnosis is eligible, in most states in the United States, for intensive intervention services. With the knowledge that these services exist and can be provided and that, if provided, outcomes are likely to improve, it is substantially less difficult to make and provide an ASD diagnosis to a child than it was 25-30 years ago.
Potentially further escalating the numbers has been the inclusion of Asperger’s Syndrome among the Pervasive Developmental Disorders. Formerly, some of these people were considered very bright but socially “quirky.” I think we are also recognizing that there is a genetic component to the autism spectrum disorders and we are very cognizant that younger siblings of autistic children may be at high risk. Screening measures are now being recommended for all children at 12-14 months of age.
There is still the issue as to whether or not there might be a role for environmental factors as a contributor to the escalating numbers. This remains a largely unanswered question to date. Happily, some very good research is in progress to address this question. If environmental factors are important, we need to define which ones and to determine if some children/families may be a higher risk than others with regard to the effects of exposure to certain environmental substances.
Do auto-immune factors play a role in the development of autism?
This is a very interesting and potentially important area of investigation in autism. Research into the possible role of immune factors is relatively new and can best be described as a “work in progress.” Several research groups are working to advance our knowledge in this area. The M.I.N.D. Institute at UC Davis in Sacramento, California has been looking at antibodies and autoantibodies in mothers having ASD children. Another group at Johns Hopkins in Baltimore, Maryland has been looking at postmortem brain tissue and the role of “inflammation” and the immune system in the etiology of autism. Both of these groups, as well as others, are looking at the role of prenatal immune factors and their potential effect on brain development. Anatomical studies of the postmortem brain, including our own, strongly suggest that ASD has its onset before birth. The fact that symptoms do not immediately become evident at birth probably reflects the fact that the brain circuitry that is disordered in autism is not fully operational and functional at birth and only comes “on line” over time, as the result of the developmental process in the brain. It is certainly possible that a subset of ASD persons may develop the syndrome as the result of immune factors and their impact on brain development, but no definitive answers are as yet available.
Where would you like to see research develop from where we are now?
Most of us who are involved in either clinical or basic science, as it relates to autism and regardless of our area of expertise or the technology that we are using, are looking at the end-product of events that probably began before birth. Thus, cranial imaging, neurophysiological measures using EEG or MEG, genetic research on ASD subjects and their families, language, cognitive, behavioral or motor assessments, as well as neurochemical and neuroanatomical studies of postmortem brain, are all looking at the “down-stream effect” of events that were probably set in motion very early in life. While these studies are extremely valuable with regard to what they can tell us about correlations between neurobiology and function, for the most part they tell us very little about how the ASD process might have begun. This is where I would like to see future research devote more of its efforts. Some research groups are beginning to look for potential early biomarkers, through studies of maternal blood during pregnancy, and from placental and umbilical cord blood obtained from the high risk child (usually an autism sibling) at birth. It will be interesting to see where some of these investigations begin to take us.
Is there still a lot that science needs to find out about what is happening as the brain is developing in utero?
Yes, there is much that we still don’t know, and that fact that ASD appears to be heterogeneous in its causes and its clinical presentation, makes the challenge of understanding the autistic brain all the greater. I believe that we are making progress as we begin to better define and look at subsets of ASD persons clinically. However, it must be said that, while we lack a good deal of knowledge about the autistic brain, we know almost nothing about other organ systems in this disorder. As we begin to look at the ASD population more broadly, it is becoming clear that multiple organ systems appear to be involved, at least in a significant subset of ASD persons. In recent years, for example, abnormalities of the gastrointestinal tract in ASD have captured the interest of more researchers. Most of the neurotransmitters present in the brain are also present in the gut. In fact, Serotonin, a neurotransmitter long of interest in autism, is generated in the gut. In addition, there is now some evidence, based on some research from Vanderbilt University Medical Center, that the MET gene may be a marker for the presence of gastrointestinal disorders in ASD persons. There is also some evidence that a subset of ASD children may also have mitochondrial disorders which would suggest that the children so affected would of necessity, be genetically different and distinct from those without a mitochondrial dysfunction. Other medical avenues that may be important in the overall health of the ASD person as well as expanding our understanding of the biology of the disorder include hormonal factors, the role of allergies, sleep disturbances, and obstructive airways due to enlarged tonsils and adenoids to name a few. By looking more closely at these and other organ systems, it is possible that we might learn more about the neurobiology of ASD as a whole, and this may help us further clinically phenotype groups of ASD persons into more cohesive subgroups for study. In addition, many of the disorders of these other organ systems are treatable. By dealing with these medical issues, those affected will feel better from a health perspective, and as a result, are likely to do better in their programs and therapies.
What are you currently working on in your own research?
I am involved in both clinical research and basic science research. Our basic research over the past 25 years has been devoted to the study of the postmortem autistic brain. Currently, we are collaborating with a group in Rome, Italy on a study related to the potential effect of estrogen as a neuroprotective substance. Our colleagues in Rome have an animal model in which the Purkinje cells of the cerebellum in their female rats appear to be preserved while those in the males are markedly decreased in number. Purkinje cells are the brain’s primary inhibitory neurons. In most of the human autistic brains studied to date, there has been a marked decrease in the number of these Purkinje cells. At this time, it is not known whether they never arrived to their final destination in the brain during development or whether something happened to them after they arrived at their final location in the cerebellum. Thus, given the sex differences in the rodent model, the question being asked is, “Is estrogen neuro-projective?” If it is, even partially, might this explain why there are more males than females affected with ASD? Our role in this project is to the study the Purkinje cell populations of both male and female postmortem ASD brain and age and sex-matched controls and to compare our results with that observed in the animal model.
We are also working with colleagues at Duke University who are interested in auditory gaiting. This study has to do with auditory sensitivities, symptoms which are often observed in ASD. The Duke researchers have created an animal model in which auditory gaiting is impaired and then have tried to correct it through the use of medications. Our role is to examine the rodent brains from these animals, both treated and untreated, to determine what microscopic structural abnormalities might exist to explain the behavioral findings. The ultimate goal is to try to define therapies that might help ASD persons and others who may have significant auditory sensitivities.
Additional studies include collaborations with Dr. Gene Blatt, one of our colleagues at Boston University School of Medicine, in which we are looking at the anterior cingulum, cerbellum and language areas in the postmortem autistic brain in comparison with controls.
On the clinical side, we have a baby siblings project in conjunction with the Kennedy Krieger Institute in Baltimore, MD. In these studies, we are assessing younger siblings of children with autism. We are in the second stage of this project. The first stage was to evaluate these autism siblings from ages 6 months – 3 years. We are now looking at the same group of children at ages 4 – 8 years to evaluate development outcomes over time.
We are also involved with colleagues at Vanderbilt University Medical Center with regard to the gastrointestinal tract and the role of the MET gene. We are also part of the Boston Autism Consortium, a group involving all of the major teaching hospitals in the Boston area, in a project devoted to the genetic analysis of ASD children and their families. In addition, we are involved in a number of projects under the auspices of the Autism Treatment Network (ATN), a group of academic centers in the United States and Canada, dedicated to the investigation of medical disorders which may be co-morbid in autism.
Has any recent research made a casual relationship that some cases of autism are manifestations of early onset bipolar disorder?
There was an early study conducted by G. Robert DeLong, MD, then at Duke University, in which there appeared to be a connection between the presence of family members with bipolar disorder and depression and the prevalence of ASD children in these same families. This is a pattern that continues to be observed in some of our families and may reflect a genetic risk factor in these families. More research in this area is needed before any direct conclusions can be made.
Since 1996, we have convened an annual group of closed door “Think Tanks” in which researchers from differing backgrounds and expertise come together to discuss their respective studies. It is an unusual opportunity to hear from others outside of one’s own area of interest and to see how differing pieces of the research puzzle may begin to fit together into a whole. The group usually consists of representatives from 15-20 labs from the United States and Canada. It is our hope that each will learn from the other and that collaborations will develop to benefit the field as a whole.
Did anything interesting come out of this year’s annual meeting?
We heard more about the studies related to immune factors. We also learned more about the estrogen work from the group in Rome and about the potential role of mitochondrial disorders in ASD. We heard about the studies from the Johns Hopkins group relative to their findings and probable significance of the presence of inflammatory abnormalities in the autistic brain and more about the role of Gamma Amino Butyric Acid (GABA), the brain’s primary inhibitory neurotransmitter. My belief if that we, as research scientists and clinicians can no longer work in our respective silos. That approach isn’t working. We need to learn what others are doing and increase our interdisciplinary collaborations in order to begin to solve the puzzle of autism. That is what this meeting is all about and I am pleased to be able to report that many collaborations have been developed as a result of these gatherings and several important papers have been published as a result. I hope there will be many more.
Do you think the solution to the puzzle of autism is near or may we not find the key for many years?
Over the past 20-25 years, the field has grown enormously, thanks to greater awareness and more research funding. However, we still have a very long way to go. As mentioned previously, autism is a behaviorally defined syndrome that probably results from multiple different causes. Because of the marked clinical variability among those with the disorder, we need to do a much better job defining our study populations into specifically characterized subgroups. We need to begin to include medically defined subtypes in the description of our study populations – for example those with and without gastrointestinal disorders, those with or without sleep disturbances and so on. Are we including males or females (there is some thought that females with ASD may be biologically different than males with ASD), what age groups should be included and why, and are siblings really “controls?” In short, we need to be more precise when describing our study populations, and descriptors should go beyond language, behavior, and cognition which is primarily what has been described up to this point.
What hopeful message would you like to leave for parents?
I think that the emphasis on early identification has made an extremely important difference in how we evaluate and treat children with autism and what our outcome expectations are. The idea that we recognize that younger siblings are at risk, that the field has recognized that, even if you are not a younger autism sibling, if you have some of these early risk signs, a diagnosis can be made and intensive services implemented. There is growing evidence that early identification and intervention can have a very positive effect on developmental outcomes. Unfortunately, good outcomes are not uniform across the spectrum but it is far better than we have been able to achieve in the past. I think that this has been the biggest change over the last few years and I would anticipate continued gains in this area as we learn more about effective interventions in the future. There is a growing subset of children now, who by ages 5, 6 and 7 years, appear to have left their diagnosis behind. Dr. Deborah Fein, PhD, Neuropsychologist at the University of Connecticut recently spoke at our recent “Current Trends in Autism” conference (Natick, Massachusetts) and is currently conducting a study that involves the evaluation of the children who appear to no longer meet the criteria for autism. What is different about those children and why did they succeed whereas others have not? We have more ASD children going on to college, growing up and getting married, and it has been really fun to watch this happen. On the more discouraging side, we still have a small subset of ASD children who, no matter what we do or how much intervention has been provided, simply don’t make effective progress. What is it that is holding these children back? These are the children who really bother me. I worry that there must be some other disorder that is complicating their clinical picture or getting in the way of progress that we are missing and haven’t figured out yet. If I have one thing that keeps me up at night, this is probably it.
The hopeful story is that early diagnosis, early treatment and intensive services with high quality, experienced professionals, can really turned around many autistic children and can result in much brighter futures for these children and their families. I think this is just really thrilling and wonderful.
Margaret L. Bauman, MD, is associate professor of neurology at Harvard University Medical School; adjunct associate professor of anatomy and neurobiology at Boston University School of Medicine; associate pediatrician and assistant neurologist at Massachusetts General Hospital, and medical director of the Autism Treatment Network. She also directs the Lurie Family Autism Center/Learning and Developmental Disabilities Evaluation and Rehabilitation Services (LADDERS), a satellite multidisciplinary clinic of the Massachusetts General Hospital for Children, and both the Autism Research Foundation and the Autism Research Consortium. In California, Dr. Bauman serves as a child neurology consultant for the Casa Colina Centers for Rehabilitation, Inc, in Pomona, California; and a volunteer physician for the department of pediatrics at the University of California, Irvine. Her research interests include the study of the microscopic brain structure in autism, Rett syndrome and other disorders of neurological development. Bauman has over 75 scientific publications, including peer-reviewed journal articles, book chapters and books. The 2nd edition of her acclaimed book, “The Neurobiology of Autism,” co-edited with T.L. Kemper, was released in January 2005. Her many honors include the 2005 Doug Flutie Junior Award, the 2004 Autism Society of Ontario’s Stacy Lynne McNeice Memorial Lecture Award, and the 2003 Pediatric Therapy Network’s Ivory Tower Award for connecting basic science to clinical practice in the field of autism.